Prevention of chronic renal allograft rejection by AS2553627, a novel JAK inhibitor, in a rat transplantation model

• Published in: Transplant immunology Vol. 46; pp. 14 - 20
• Main Authors: Nakamura, Koji, Kawato, Yuka, Kaneko, Yoko, Hanaoka, Kaori, Kubo, Kaori, Nakanishi, Tomonori, Maeda, Masashi, Fukahori, Hidehiko, Ito, Misato, Noto, Takahisa, Inami, Masamichi, Hirose, Jun, Morokata, Tatsuaki
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2018
• Subjects: Chronic rejection; JAK inhibitor; Renal transplantation; Tacrolimus; TIMP-1; Chronic rejection; MHC; TYK2; EMT; ECM; CsA; KIM-1; GFR; DSA; Tacrolimus; JAK; TAC; Renal transplantation; JAK inhibitor; IF/TA
• ISSN: 0966-3274; 1878-5492
• DOI: 10.1016/j.trim.2017.10.001

Janus kinase (JAK) inhibitors are thought to be promising candidates to aid renal transplantation. However, the effectiveness of JAK inhibitors against features of chronic rejection, including interstitial fibrosis/tubular atrophy (IF/TA) and glomerulosclerosis, has not been elucidated. Here, we investigated the effect of AS2553627, a novel JAK inhibitor, on the development of chronic rejection in rat renal transplantation. Lewis (LEW) to Brown Norway (BN) rat renal transplantation was performed. Tacrolimus (TAC) at 0.1mg/kg was administered intramuscularly once a day for 10 consecutive days starting on the day of transplantation (days 0 to 9) to prevent initial acute rejection. After discontinuation of TAC treatment from days 10 to 28, AS2553627 (1 and 10mg/kg) was orally administered with TAC. At 13weeks after renal transplantation, grafts were harvested for histopathological and mRNA analysis. Creatinine and donor-specific antibodies were measured from plasma samples. Urinary protein and kidney injury markers were also evaluated. AS2553627 in combination with TAC exhibited low plasma creatinine and a marked decrease in urinary protein and kidney injury markers, such as tissue inhibitor of metalloproteinase-1 and kidney injury molecule-1. At 13weeks, histopathological analysis revealed that AS2553627 treatment inhibited glomerulosclerosis and IF/TA. In addition, upregulation of cell surface markers, fibrosis/epithelial–mesenchymal transition and inflammation-related genes were reduced by the combination of AS2553672 and TAC, particularly CD8 and IL-6 mRNAs, indicating that AS2553627 prevented cell infiltration and inflammation in renal allografts. These results indicate the therapeutic potential of JAK inhibitors in chronic rejection progression, and suggest that AS2553627 is a promising agent to improve long-term graft survival after renal transplantation. •The effect of AS2553627, a JAK inhibitor, on chronic rejection was investigated in rat renal transplantation model.•AS2553627 improved kidney dysfunction and inhibited interstitial fibrosis/tubular atrophy and glomerulosclerosis.•AS2553627 also reduced intragraft fibrosis/epithelial–mesenchymal transition and inflammation-related gene expression.